Function of microRNA in pro-inflammatory gene expression

炎症是身体对感染或损伤的自然保护性反应，但不正常或不受控制 炎症反应弊大于利。在适当的监管方面的崩溃 炎症是一系列常见疾病的基础，如类风湿性关节炎、炎症性肠炎 疾病、多发性硬化症和感染性休克。细胞表达促炎基因的研究进展 免疫系统是炎症发展过程中最关键的一步。尽管取得了重大进展 目前，促炎症基因表达的机制仍不完全清楚。长的- 这项建议的术语目标是了解microRNA的调节和功能 (MiRNA)是新近发现的一组短小的非编码单链RNA，在PRO-2的表达中起重要作用。 炎症基因。已知的促炎基因，如肿瘤坏死因子、白介素1和 环氧合酶2在多个基因表达水平上受到控制，其中最重要的一个是 在当时的mRNA稳定性的调节。这些致炎基因的快速RNA降解服务于 作为一种控制促炎分子水平的机制。富Au元素(ARE)位于 这些短暂的mRNAs的3‘非翻译区决定了它们的降解。我们最近的研究表明 DICER和ARGANUTE(AGO/eif2C)家族成员，参与microRNA(MiRNA)加工的组件 和功能，是含有ARE的信使核糖核酸(ARE-mRNAs)快速衰退所必需的。此外，我们 发现miR16，一个具有与ARE序列部分互补的序列的人miRNA，为 是Are-mRNA周转所必需的。MiR16在静息细胞ARE-mRNA衰变中的需求表明 MiR16的一种生理“内务”功能，可防止基础水平较高的促炎因子 基因表达。这项建议概述了对miRNA调节细胞因子基因机制的研究。 表达，重点是炎症刺激如何通过阻断ARE-mRNA而使其稳定 MiRNA介导的mRNA降解。在这个研究计划中，我们还将评估细胞的整体功能 通过对miR16靶基因进行全基因组鉴定和分类。为了实现我们的目标，我们将 综合运用遗传、生物化学和分子生物学方法。中提议的工作 这一应用将有助于更好地理解促炎基因的表达。理解 MiRNA在促炎基因的mRNA稳定性中的作用应为 开发新型消炎药。

Inflammation js the body's natural protective response to infection or injury, but abnormal or uncontrolled inflammatory responses can do more harm than good. A breakdown in the appropriate regulation of inflammation underlies a wide range of common diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and septic shock. The expression of pro-inflammatory genes by cells in the immune system is the most crucial step in the development of inflammation. Although significant progress has been made, the mechanism of pro-inflammatory gene expression is still not fully understood. The long- term objective of this proposal is to gain an understanding of the regulation and function of microRNA (miRNA), a newly identified group of short non-coding single-stranded RNA, in the expression of pro- inflammatory genes. It is knownthat pro-inflammatory genes such as tumor necrosis factor, interleukin-1, arid cyclooxygenase 2 are controlled at multiple levels of gene expression, one of the most important of which is at the regulation of then- mRNAstability. Quick mRNAdegradation of these pro-inflammatorygenes serves as a mechanism to control the level of pro-inflammatory molecules. AU-rich elements (AREs) located in the 3' untranslated region of these short-lived mRNAs dictate their degradation. Ourrecent study revealed that Dicer and Argonaute (Ago/eif2C) family members, components involved in microRNA(miRNA) processing and function, are required for the rapid decay of mRNA that contain AREs (ARE-mRNA). Furthermore, we found miR16, a human miRNAwith a sequence that is partially complementaryto the ARE sequence, to be required for ARE-mRNAturnover. The requirement of miR16 in ARE-mRNA decay in resting cells suggests a physiological 'housekeeping' function of miR16 in which it prevents high basal levels of pro-inflammatory gene expression. This proposal outlines a study into the mechanism of miRNA-regulated cytokine gene expression, with an emphasis on how inflammatory stimuli induce stabilization of ARE-mRNA by blocking miRNA-mediated mRNA degradation. In this research plan, we will also evaluate the overall function of miR16 by genome-wide identifying and classifying of miR16-targeted genes. To achieve our aims, we will utilize a combination of genetic, biochemical, and molecular biological approaches. The work proposed in this application will contribute to a better understanding of pro-inflammatory gene expression. Understanding the function of miRNA in mRNA stability of pro-inflammatory genes should provide new avenues for developing novel anti-inflammatoryagents.